Two potential animal models of HIV-1 induced disease have been evaluated. In the first, a chimpanzee was simultaneously inoculated with large amounts of three different primary HIV-1 isolates (HIV-1DH12 , HIV-1DH20, and HIV-1DH29) as both cell-free and cell-associated virus. During the primary infection, HIV-1DH12 was isolated directly from the plasma and HIV-1DH20 DNA was detected following amplification of PBMC DNA between weeks 9 and 11. Following resolution of the initial infection, the immune system of the infected chimpanzee was stimulated by two infusions of human PBMCs at weeks 23 and 28 post inoculation. This resulted in the appearance of HIV-1DH29 in lymphocytes recovered from a lymph node biopsy. The subsequent administration of high doses of steroids induced a plasma viremia at weeks 48 and 70, marked elevations of ELISA antibody levels, and increased numbers of PBMC carrying copies of HIV-1 DNA. In the second, seven cynomolgus macaques, one rhesus macaque, and two pig-tailed macaques have been inoculated with the HIV-1/SIV chimeric virus (SHIV) that carries the vpr-tat-rev-vpu-env-nef gene region from the HIV-1DH12 isolate (and designated SHIVmad1). All of the monkeys became infected. One of cynomolgus monkeys exhibited significant drop of CD4+ cells (less than 100 cells/mul blood) which has persisted for more than a year. This monkey has recently developed a wasting syndrome beginning approximately 60 weeks after inoculation, which has resulted in a loss of more than 30% body weight. Some of the other monkeys have exhibited a transient drop of CD4 cells, and one of the pig-tailed macaques has experienced a gradual decrease of CD4 positive lymphocytes (16 weeks post inoculation). Two cynomolgus macaques have recently been transfused with blood from the animal with low CD4 cell levels. Since the SHIVs isolated from several of the infected monkeys replicate more rapidly and to higher titers than the original virus, several molecular clones corresponding to these viruses have been obtained and are being evaluated for infectivity in both tissue culture systems and in vivo. Some of the persistently infected macaques with relatively low virus load and no CD4 depletion are being treated with immunosuppressive agents in an attempt to increase levels of circulating SHIV.